Second Generation Antipsychotic Agents

Until the past decade, acute EPS (and its pervasive adverse consequences) and tardive dyskinesia were considered unavoidable by-products of schizophrenia treatment—in fact, it was believed that there could be no antipsychotic efficacy without EPS. Over the past decade, five "atypical" or novel antipsychotic agents have been introduced into clinical practice in the United States; in chronological order of introduction, these include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiap-ine (Seroquel), and ziprasidone (Geodon). What principally distinguishes these newer antipsychotic agents from the older conventional agents is their ability to achieve an antipsychotic effect at least as good as that achieved by conventional agents with a much lower risk of EPS (Meltzer, 1995). In fact, this second generation of antipsychotics is called "atypical" because of its better ability to separate antipsychotic effect from extrapyramidal side effect (Fig. 10.2). The newer generation of antipsychotic agents thus clearly demonstrate important advantages over conventional agents in the area of EPS and tardive dyskinesia (Tandon et al., 1999a).

In addition to possessing at least equivalent efficacy to first-generation antipsy-chotics in treating positive symptoms, the newer generation of agents appears to provide greater efficacy in the other domains—notably negative symptoms, cognition, and mood. Much of the greater efficacy in these domains appears to be related to their ability to achieve an antipsychotic effect in the absence of EPS (Fig. 10.3). Consequently, it is essential that atypical agents be dosed in such a manner that they produce an antipsychotic effect in the absence of EPS, without the need for any anticholiner-gic or other antiparkinsonian medication, thereby preserving the broader efficacy and lower risk of tardive dyskinesia associated with their use (Kane et al., 1993; Jibson and Tandon, 2000).

Finally, in addition to their broader spectrum of efficacy and lower risk of neurological adverse effects, the newer generation of antipsychotics has greater efficacy than conventional antipsychotics in otherwise treatment-refractory patients (Kane et al., 1988). Among the five atypical agents, clozapine has the best proven track record in this regard (Chakos et al., 2001).

Ziprasidone Haloperidol Risperidone

Ziprasidone Haloperidol Risperidone

Figure 10.2. Comparative pharmacology of atypical antipsychotic drugs. [Adapted from Schmidt et al. (1998). Soc Neurosci Abstr 24(2): 2177.] See ftp site for color image.

Figure 10.3. Dose-response curve: Antipsychotic effect vs. EPS. (Adapted from Jibson and Tandon, 1998.)

Figure 10.3. Dose-response curve: Antipsychotic effect vs. EPS. (Adapted from Jibson and Tandon, 1998.)

While the second generation of antipsychotics possesses several advantages over the first generation of conventional antipsychotics, and their introduction into clinical practice represents a significant advance in the pharmacotherapy of schizophrenia, they also have several limitations both with regard to safety/tolerability and to efficacy. Differences in the pharmacological profiles of these second-generation antipsychotics (Fig. 10.4 and Table 10.1) translate into differences in their side effect profiles (Table 10.2 and 10.3). Each available novel antipsychotic agent has a distinctive adverse effect profile; a comparison between them and two representative conventional agents (thioridazine and haloperidol) with regard to key side effects is provided in Table 10.4.

TABLE 10.1. Pharmacological Profile of Atypical Antipsychotics

Receptor Blockade

All dopamine D2 receptor blockade deliberately add serotonin 5-HT2A receptor blockade that is more potent then D2 blockade. What else they add differs? Clozapine: several properties (D1, D2, D3, D4, 5-HT2A, 5-HT3, ACh, H1, NE) Risperidone: D2 + 5-HT2A + alpha-1 NE Olanzapine: D2 + 5-HT2A + alpha-1 NE + M1 + H1 Quetiapine: D2 + 5-HT2A + alpha-1 NE + H1 Ziprasidone: D2 + 5-HT2A + (increased NE, 5-HT, 5-HT1A) Aripiprazole: D2 partial agonist + 5-HT2A

TABLE 10.2. Clinical Implications of Blockade of Various Receptors

Possible Side

Receptors Possible Benefits Effects

Dopamine D2 receptor

Antipsychotic effect Efficacy on positive symptoms Efficacy on agitation

Extrapyramidal movement disorders (EPS), (dystonia, tremor, akathisia, tardive dyskinesia) Endocrine changes (prolactin elevation causing galactorrhea, gynecomastia, menstrual changes, sexual dysfunction)

TABLE 10.3. Clinical Implications of Blockade of Various Receptors

Established

Likely Side

Receptors

Benefits

Effects

Serotonin 5-HT receptors

5-HT2A receptor

Reduced EPS

??

5-HT2A receptor

Not definitely known

Weight gain

Histamine H1 receptor

Not definitely known

Sedation, Weight gain

Muscarinia receptor

Not definitely known

Blurred vision, dry mouth, constipation,

urinary retention, sinus tachcardia,

memory dysfunction

a1-Adrenergic receptor

Not definitely known

Postural hypotension, dizziness

TABLE 10.4. Conventional vs. Atypicals: Side Effect Profiles

ZIP

THZ

HAL

CLZ

RIS

OLZ

QTP

EPS

0 to ±

+

+ + +

0 to ±

0 to ±

0 to ±

0 to ±

Dose-related EPS

+

++

+ + +

0

++

+

0

TD (tardive dyskinesia)

±

+ + +

+ + +

0

±

±

±

Prolactin elevation

±

++

+ + +

0

++

±

±

Agranulocytosis

±

±

±

++

±

±

±

Anticholinergic

±

+ + +

±

+ + +

±

±

±

AST/ALT elevation

±

+

+

+

±

+

±

Hypotension

+

+ + +

+

+ + +

++

+

++

Sedation

+

+ + +

+

+ + +

+

++

++

QTc prolongation

+

++

±

+

±

±

±

Weight gain

±

+

+

+ + +

++

+ + +

++

Key: 0 = absent; ± = minmal; + = mild; ++ = moderate; + + + = severe. Source: Tandon et al. (1991a).

Key: 0 = absent; ± = minmal; + = mild; ++ = moderate; + + + = severe. Source: Tandon et al. (1991a).

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